US7795459B2 - Paricalcitol purification - Google Patents
Paricalcitol purification Download PDFInfo
- Publication number
- US7795459B2 US7795459B2 US12/431,068 US43106809A US7795459B2 US 7795459 B2 US7795459 B2 US 7795459B2 US 43106809 A US43106809 A US 43106809A US 7795459 B2 US7795459 B2 US 7795459B2
- Authority
- US
- United States
- Prior art keywords
- paricalcitol
- purified
- filtration
- recovered
- high vacuum
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 title claims abstract description 39
- 229960000987 paricalcitol Drugs 0.000 title claims abstract description 36
- 238000000746 purification Methods 0.000 title description 5
- 238000002425 crystallisation Methods 0.000 claims abstract description 10
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 9
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 9
- 238000001665 trituration Methods 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims 2
- 239000012265 solid product Substances 0.000 claims 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract 1
- 238000001291 vacuum drying Methods 0.000 abstract 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 abstract 1
- KJKIIUAXZGLUND-ICCVIKJNSA-N 25-hydroxyvitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C KJKIIUAXZGLUND-ICCVIKJNSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- FUBPRYXDIHQLGH-NAWOPXAZSA-N (1r,3ar,4s,7ar)-1-[(2s)-1-hydroxypropan-2-yl]-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-4-ol Chemical compound O[C@H]1CCC[C@]2(C)[C@@H]([C@@H](CO)C)CC[C@H]21 FUBPRYXDIHQLGH-NAWOPXAZSA-N 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- GVELBHIEDLOFIA-DVOYKHLOSA-N [H][C@@]12CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)(C)O)[C@@]1(C)CCC/C2=C\C=C1C[C@@H](O)C[C@H](O)C1.[H][C@@]12CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)(C)O)[C@@]1(C)CCC/C2=C\C=C1\C[C@@H](O)CCC1=C.[H][C@]12CCCC(O)[C@@H]1CC[C@@H]2[C@H](C)CO Chemical compound [H][C@@]12CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)(C)O)[C@@]1(C)CCC/C2=C\C=C1C[C@@H](O)C[C@H](O)C1.[H][C@@]12CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)(C)O)[C@@]1(C)CCC/C2=C\C=C1\C[C@@H](O)CCC1=C.[H][C@]12CCCC(O)[C@@H]1CC[C@@H]2[C@H](C)CO GVELBHIEDLOFIA-DVOYKHLOSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
Definitions
- This invention relates to the vitamin D analog paricalcitol, and more particularly to methods for its purification.
- Paricalcitol (1) is a synthetically manufactured vitamin D analog developed for the treatment of secondary hyperparathyroidism associated with chronic renal failure.
- the present invention provides a simple process for the purification of crude paricalcitol into API quality material. It comprises crystallization of solid impure paricalcitol from solution in isopropyl acetate. Recovery of paricalcitol is usually greater than 80%. Purity of the isolated material is usually greater than 99.7%, and the amount of C20 epimer is reduced by at least 60%. Particularly impure samples can be purified by successive such crystallizations.
- Isopropyl acetate appears to be unique among industrially acceptable solvents in its ability to dissolve paricalcitol at temperatures close to the boiling point of the solvent and selectively precipitate paricalcitol on cooling, in this high degree of purity, to the substantially complete exclusion of other isomers. Moreover, this solvent is suitably volatile, relatively inexpensive, safe and non-toxic, with a high degree of pharmaceutical industry acceptability.
- solid impure paricalcitol is preferably dissolved in isopropyl acetate at reflux temperatures, and crystallization is achieved by cooling the solution to room temperature or below.
- a solvent to substrate ratio of about 40:1 to 60:1, preferably about 50:1 (v/w) is suitably used.
- the solid impure paricalcitol is preferably obtained by trituration of crude paricalcitol with tert-butyl methyl ether followed by filtration.
- MTBE is a particularly desirable medium for the trituration, on account of its acceptable volatility (leaving little residue) and its industry acceptability.
- Paricalcitol prepared as in Example 1 was suspended in isopropyl acetate (240 mL) and refluxed until all solids had dissolved. The resulting solution was filtered hot, and precipitation was immediately observed. The suspension was allowed to cool down to ambient temperature over a 2 h period, after which it was cooled to 4° C. (refrigerator) for 1.5 h. The solids were collected by filtration and dried under high vacuum at room temperature for 18 h to give Paricalcitol as a crystalline white powder (4.59 g, 86% recovery), with 99.87% purity, as determined by HPLC.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Paricalcitol, a synthetic vitamin D analog, is purified to a purity greater than 99.7% by crystallization from solution in isopropyl acetate solvent, followed by filtration and vacuum drying. Isopropyl acetate appears to be unique among commonly available and pharmaceutically acceptable solvents in its ability to precipitate paricalcitol in this high purity, essentially free of isomers thereof.
Description
This invention relates to the vitamin D analog paricalcitol, and more particularly to methods for its purification.
Paricalcitol (1) is a synthetically manufactured vitamin D analog developed for the treatment of secondary hyperparathyroidism associated with chronic renal failure.
The known synthetic route to paricalcitol utilizes 25-hydroxyvitamin D2 (2) as the key starting material, but this compound is quite costly and has very limited commercial availability. As a result, alternative syntheses to compound 2 and its derivatives have been developed, mostly based on the functionalization of the Inhoffen-Lythgoe diol (3).
Such approaches involve a significant number of complex chemical transformations, with formation of several impurities, many of which carry through to the final active pharmaceutical ingredient (API). Of particular concern is the C20 epimer of paricalcitol, so similar in structure that even the HPLC analytical method listed in the United States Pharmacopeia fails to resolve both compounds.
U.S. Pat. Nos. 5,281,731 and 5,086,191 describe the purification of paricalcitol by preparative HPLC, but the cost and labor associated with this method make it undesirable for large scale manufacturing. More recently, published patent application US 2007/0093458 discloses crystallization procedures for the purification of paricalcitol. However, the examples given produce material of insufficient purity and/or in relatively low yields. Furthermore, the procedures described are volumetrically inefficient and many of them also require precise control of solvent ratios, volumes and temperatures.
The present invention provides a simple process for the purification of crude paricalcitol into API quality material. It comprises crystallization of solid impure paricalcitol from solution in isopropyl acetate. Recovery of paricalcitol is usually greater than 80%. Purity of the isolated material is usually greater than 99.7%, and the amount of C20 epimer is reduced by at least 60%. Particularly impure samples can be purified by successive such crystallizations.
Isopropyl acetate appears to be unique among industrially acceptable solvents in its ability to dissolve paricalcitol at temperatures close to the boiling point of the solvent and selectively precipitate paricalcitol on cooling, in this high degree of purity, to the substantially complete exclusion of other isomers. Moreover, this solvent is suitably volatile, relatively inexpensive, safe and non-toxic, with a high degree of pharmaceutical industry acceptability.
In the process, solid impure paricalcitol is preferably dissolved in isopropyl acetate at reflux temperatures, and crystallization is achieved by cooling the solution to room temperature or below. A solvent to substrate ratio of about 40:1 to 60:1, preferably about 50:1 (v/w) is suitably used. The solid impure paricalcitol is preferably obtained by trituration of crude paricalcitol with tert-butyl methyl ether followed by filtration. MTBE is a particularly desirable medium for the trituration, on account of its acceptable volatility (leaving little residue) and its industry acceptability.
Crude Paricalcitol (3.84 g, theoretical Paricalcitol content 3.1 μg) was triturated with MTBE (75 mL) at room temperature for 30 minutes, collected by filtration and washed with additional MTBE (20 mL). After drying under high vacuum at room temperature for 24 h, Paricalcitol was isolated as a white solid (2.67 g, 85% yield).
Paricalcitol prepared as in Example 1 (5.34 g) was suspended in isopropyl acetate (240 mL) and refluxed until all solids had dissolved. The resulting solution was filtered hot, and precipitation was immediately observed. The suspension was allowed to cool down to ambient temperature over a 2 h period, after which it was cooled to 4° C. (refrigerator) for 1.5 h. The solids were collected by filtration and dried under high vacuum at room temperature for 18 h to give Paricalcitol as a crystalline white powder (4.59 g, 86% recovery), with 99.87% purity, as determined by HPLC.
Claims (14)
1. A process for purifying paricalcitol, which comprises:
i. dissolving a solid impure paricalcitol composition in isopropyl acetate solvent;
ii. and recovering purified paricalcitol from the solution by crystallization.
2. The process of claim 1 wherein the dissolution in isopropyl acetate is conducted at elevated temperature, and crystallization is achieved by cooling.
3. The process of claim 2 wherein the dissolution takes place under reflux and cooling is conducted to room temperature or below.
4. The process of claim 1 wherein the solid impure paricalcitol composition is the solid product resulting from trituration of crude paricalcitol with t-butyl methyl ether.
5. The process of claim 4 wherein the trituration takes place at room temperature.
6. The process of claim 1 wherein the recovered paricalcitol is subjected to a second crystallization from isopropyl acetate.
7. The process of claim 6 wherein the purified paricalcitol is recovered by filtration and subsequently dried under high vacuum.
8. The process of claim 1 wherein the solvent to substrate ratio in the crystallization step is from about 40:1 to about 60:1 (v/w).
9. The process of claim 1 wherein the purified paricalcitol is recovered by filtration and subsequently dried under high vacuum.
10. The process of claim 3 wherein the purified paricalcitol is recovered by filtration and subsequently dried under high vacuum.
11. The process of claim 5 wherein the purified paricalcitol is recovered by filtration and subsequently dried under high vacuum.
12. The process of claim 3 wherein the solid impure paricalcitol composition is the solid product resulting from trituration of crude paricalcitol with t-butyl methyl ether.
13. The process of claim 12 wherein the trituration takes place at room temperature.
14. The process of claim 13 wherein the purified paricalcitol is recovered by filtration and subsequently dried under high vacuum.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002673905A CA2673905A1 (en) | 2008-09-11 | 2009-07-24 | Paricalcitol purification |
| US12/543,600 US8013176B2 (en) | 2008-09-11 | 2009-08-19 | Paricalcitol purification |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2639477A CA2639477C (en) | 2008-09-11 | 2008-09-11 | Paricalcitol purification |
| CA2639477 | 2008-09-11 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US12/543,600 Continuation-In-Part US8013176B2 (en) | 2008-09-11 | 2009-08-19 | Paricalcitol purification |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| US20100063330A1 US20100063330A1 (en) | 2010-03-11 |
| US7795459B2 true US7795459B2 (en) | 2010-09-14 |
Family
ID=41799838
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US12/431,068 Active US7795459B2 (en) | 2008-09-11 | 2009-04-28 | Paricalcitol purification |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US7795459B2 (en) |
| CA (2) | CA2639477C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102010062347A1 (en) | 2010-04-09 | 2011-12-01 | Evonik Degussa Gmbh | Polymer powder based on polyamides, use in a molding process and molding, made from this polymer powder |
| CN107540588B (en) * | 2016-06-24 | 2019-08-27 | 江苏神龙药业股份有限公司 | The preparation method of paricalcitol |
| CN107540587B (en) * | 2016-06-24 | 2019-11-22 | 江苏神龙药业股份有限公司 | The purification process of paricalcitol |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5086191A (en) | 1991-05-28 | 1992-02-04 | Wisconsin Alumni Research Foundation | Intermediates for the synthesis of 19-nor vitamin D compounds |
| US5281731A (en) | 1991-05-28 | 1994-01-25 | Wisconsin Alumni Research Foundation | Synthesis of 19-nor vitamin D compounds |
| WO2007011951A2 (en) | 2005-07-18 | 2007-01-25 | Teva Pharmaceutical Industries Ltd. | Purification of paricalcitol |
| US20070093458A1 (en) | 2005-07-18 | 2007-04-26 | Anchel Schwartz | Preparation of paricalcitol and crystalline forms thereof |
| US20090275768A1 (en) * | 2008-04-30 | 2009-11-05 | Formosa Laboratories, Inc. | Preparation of Paricalcitol |
-
2008
- 2008-09-11 CA CA2639477A patent/CA2639477C/en not_active Expired - Fee Related
-
2009
- 2009-04-28 US US12/431,068 patent/US7795459B2/en active Active
- 2009-07-24 CA CA002673905A patent/CA2673905A1/en not_active Abandoned
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5086191A (en) | 1991-05-28 | 1992-02-04 | Wisconsin Alumni Research Foundation | Intermediates for the synthesis of 19-nor vitamin D compounds |
| US5281731A (en) | 1991-05-28 | 1994-01-25 | Wisconsin Alumni Research Foundation | Synthesis of 19-nor vitamin D compounds |
| WO2007011951A2 (en) | 2005-07-18 | 2007-01-25 | Teva Pharmaceutical Industries Ltd. | Purification of paricalcitol |
| US20070093458A1 (en) | 2005-07-18 | 2007-04-26 | Anchel Schwartz | Preparation of paricalcitol and crystalline forms thereof |
| US20070149489A1 (en) * | 2005-07-18 | 2007-06-28 | Anchel Schwartz | Preparation of paricalcitol |
| US20090275768A1 (en) * | 2008-04-30 | 2009-11-05 | Formosa Laboratories, Inc. | Preparation of Paricalcitol |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2639477A1 (en) | 2010-03-11 |
| CA2673905A1 (en) | 2010-03-11 |
| CA2639477C (en) | 2016-03-22 |
| US20100063330A1 (en) | 2010-03-11 |
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